The compounds of the invention of formula I have not previously been described. They act on the so-called Kv1.5 potassium channel and inhibit a potassium current which is designated the ultra-rapidly activating delayed rectifier in the human atrium. In addition, the compounds also act on other atrium-specific potassium channels such as the acetylcholine-dependent potassium channel KACh, and the 2P domain potassium channel TASK-1. The compounds are therefore very particularly suitable as antiarrhythmic active ingredients, in particular for the treatment and prophylaxis of atrial arrhythmias, for example atrial fibrillation (AF) or atrial flutter.
Atrial fibrillation (AF) and atrial flutter are the commonest sustained cardiac arrhythmias. The incidence increases with increasing age and frequently leads to fatal sequelae such as, for example, stroke. AF affects for example about 3 million Americans and leads to more than 80 000 strokes each year in the USA. Although class I and III antiarrhythmics currently in use can reduce the rate of recurrence of AF, their use is restricted owing to their potential proarrhythmic side effects. There is for this reason a great medical need for better medicaments for treating atrial arrhythmias to be developed.
It has been shown that so-called reentry depolarization waves underlie most supraventricular arrhythmias. Such reentries occur if the cardiac tissue has a slow conductivity and, at the same time, very short refractory periods. The increase in the myocardial refractory period by prolonging the action potential is an accepted mechanism for terminating arrhythmias and preventing their development. The length of the action potential is substantially determined by the extent of repolarizing K+ currents which flow out of the cell through the various K+ channels. Particularly great importance is ascribed in this connection to the so-called delayed rectifier IK which consists of 3 different components: IKr, IKs and IKur.
Most known class III antiarrhythmics (for example dofetilide or d-sotalol) block predominantly or exclusively the rapidly activating potassium channel IKr which has been detected both in cells of the human ventricle and in the atrium. However, it has emerged that these compounds have an increased proarrhythmic risk when heart rates are low or normal, and the arrhythmias which have been observed are in particular those referred to as torsades de pointes. Besides this high risk, which is fatal in some cases, when the rate is low, the efficacy of IKr blockers has been found to decline under the conditions of tachycardia, which is just when the effect is required (“negative use-dependence”).
The “particularly rapidly” activating and very slowly inactivating component of the delayed rectifier IKur (=ultra-rapidly activating delayed rectifier), which corresponds to the Kv1.5 channel, is of particularly great importance for the duration of repolarization in the human atrium. Inhibition of the IKur potassium outward current thus represents, by comparison with inhibition of IKr or IKs, a particularly effective method for prolonging the atrial action potential and thus for terminating or preventing atrial arrhythmias. Mathematical models of the human action potential suggest that the positive effect of a blockade of the IKur ought to be particularly pronounced precisely under the pathological conditions of chronic atrial fibrillation (M. Courtemanche, R. J. Ramirez, S, Nattel, Cardiovascular Research 1999, 42, 477-489: “Ionic targets for drug therapy and atrial fibrillation-induced electrical remodeling: insights from a mathematical model”).
In contrast to IKr and IKs, which also occur in the human ventricle, IKur plays a significant role in the human atrium, but not in the ventricle. For this reason, if the IKur current is inhibited, the risk of a proarrhythmic effect on the ventricle is precluded from the outset, in contrast to blockade of IKr or IKs (Z. Wang et al, Circ. Res. 73, 1993, 1061-1076: “Sustained Depolarisation-Induced Outward Current in Human Atrial Myocytes”; G.-R. Li et al, Circ. Res. 78, 1996, 689-696: “Evidence for Two Components of Delayed Rectifier K+-Current in Human Ventricular Myocytes”; G. J. Amos et al, J. Physiol. 491, 1996, 31-50: “Differences between outward currents of human atrial and subepicardial ventricular myocytes”).
Antiarrhythmics which act by atrium-selective blockade of the IKur current or Kv1.5 channel have not, however, been available on the market to date. Although a blocking effect on the Kv1.5 channel has been described for numerous active pharmaceutical ingredients (for example quinidine, bupivacaine or propafenone), the Kv1.5 blockade in each of these cases represents only a side effect in addition to other main effects of the substances.
A number of patent applications in recent years have described various substances as Kv1.5 channel blockers. A compilation and detailed discussion of these substances has recently been published (J. Brendel, S. Peukert; Curr. Med. Chem.—Cardiovascular & Hematological Agents, 2003, I, 273-287; “Blockers of the Kv1.5 Channel for the Treatment of Atrial Arrhythmias”). However, all Kv1.5 blockers disclosed to date and described therein have entirely different types of structures than the compounds of the invention in this application. In addition, no clinical data on the effect and tolerability in humans have been disclosed to date for any of the compounds disclosed to date. Since experience has shown that only a small proportion of active ingredients successfully overcome all the clinical hurdles from preclinical research to the medicament, there continues to be a need for novel, promising substances.